The N-methyl-D-aspartate (NMDA) receptor family regulates various CNS functions such as synaptic plasticity; however, hypo or hyper-activation of NMDA receptors (NMDARs) is critically involved in many neurological and psychiatric conditions. To date, most therapeutic efforts have focused on inhibitors of NMDA receptor activity. However, there are other clinical indications for which an NMDA receptor potentiator is more likely to be appropriate. Presently, there are no preclinical studies of positive allosteric modulators for NMDA receptors. Recently, the joint laboratories of the two PIs discovered a family of compounds that are positive allosteric modulators (PAMs) as well as negative allosteric modulators (NAMs) of NMDARs. These agents have novel sites of action, novel mechanisms of action, and several novel patterns of activity. Their members include the first general NMDAR PAMs, and PAMs that are selective for each of the four GluN1/GluN2 subtypes. NMDAR PAMs have important therapeutic applications, such as for treating schizophrenia or enhancing cognition. Thus, these agents represent significant opportunities as neurobiological tools and are unique lead compounds for developing agents that can modulate NMDAR activity and synaptic plasticity for therapeutic benefit. Further progress in this critical field requires a muc better understanding of the mechanism of action and how that is related to pharmacological activity and receptor modulation. We propose that NMDAR PAMs act at two closely related sites to modulate receptor deactivation and desensitization. Experiments will identify these mechanisms of action of the NMDA receptor PAMs and characterize the respective pharmacophores responsible for these actions. Our goal is to resolve these relationships to provide firm ground for further drug development.